1. Field of the Invention
The invention relates to a compound synthesis method, a microarray, an acid-transfer composition, and a biochip composition.
2. Discussion of the Background
A method that synthesizes a biopolymer on a substrate has been known. For example, Fordor et al. propose a synthesis method that links a nucleic acid and an amino acid including a UV-labile protecting group to the surface of a solid, exposes a specific area of the surface of a solid by utilizing a photolithography mask to remove the protecting group, and reacts the nucleic acid or the amino acid with a nucleic acid or an amino acid including a light-labile protecting group so that the nucleic acid or the amino acid is extended (polymerized) at a specific position (see U.S. Pat. No. 5,445,934 and U.S. Pat. No. 5,744,305, for example).
According to the above method, since an oligonucleotide probe having a specific sequence and a specific length can be selectively synthesized at a specific position, the above method is useful for synthesizing oligonucleotide probes having the desired sequence and length at a specific position. Moreover, since the above method utilizes a microfabrication mask used for a semiconductor production process, the above method is very useful for synthesizing oligonucleotide probes with a high degree of integration. The above patent document discloses that a sequencing method using an oligonucleotide probe that is more convenient and faster than the Sanger method is useful for producing oligonucleotide probes with a high degree of integration.
A photolithographic process that utilizes a photoresist (PR) used to form a fine pattern in a semiconductor production process has attracted attention as indispensable technology for increasing the degree of integration of a DNA chip. Since the size and the capacity of a semiconductor chip are determined depending on the resolution employed in the photolithographic process, the photolithographic process has influenced the development of semiconductor/microelectronics. The photolithographic process utilizes a difference in solubility between the exposed area and the unexposed area of the photoresist. A system in which the solubility of the exposed area decreases is referred to as a negative-tone system, and a system in which the solubility of the unexposed area decreases is referred to as a positive-tone system. The positive-tone system is mainly used for producing a semiconductor chip. A large number of oligonucleotide probes can be arranged on a chip having a limited area by utilizing the photolithographic process. A method that utilizes a photoresist (see U.S. Pat. No. 5,658,734, for example) and a method that utilizes a micromirror have been proposed as application examples of the photolithographic process.
A photolithographic process that utilizes a photoresist (hereinafter referred to as “PR process”) has an advantage in that a material that has been developed or put on the market aimed at the semiconductor industry can be used. According to the PR process, when forming a pattern by applying light, and washing the exposed area, a normal solid-phase nucleic acid synthesis reaction occurs on the surface so that nucleotides are bound to the surface. In this case, a diazoquinone/cresol novolac resin that exhibits excellent interface adhesion is typically used as the photoresist. The diazoquinone/cresol novolac resin exhibits excellent pattern characteristics when using an i-line (365 nm), and has been used for a 16 Mbit DRAM process. A method that improves the method by providing a protective coating under the photoresist has been proposed (see J. Vac. Sci. Tech., 1989, B7(6), 1734, for example).
The PR process is roughly divided into a first stage that includes coating the photoresist, and forming a PR pattern by exposure and development, a second stage that includes removing the protecting group in the etched area, and removing the photoresist using an acid solution, and a third stage that includes sequentially bonding nucleic acid, and performing a post-treatment.
A photoacid patterned array (PPA) system has been proposed to improve the PR process (see U.S. Pat. No. 5,658,734, for example). The PPA system utilizes a polymer matrix mixed with a photoacid generator (PAG). According to the PPA system, an acid is generated only in the exposed area, and the protecting group is removed after a heat treatment. Therefore, the first stage and the second stage of the PR process can be performed in one stage.
A method that produces a DNA chip using a micromirror may be used to produce a DNA chip by utilizing photolithography. In this case, a support that can react with an oligonucleotide is formed on a solid substrate using a photoresist, and a solution of a photoacid generator is put in the support. A specific area is then exposed using the micromirror to generate an acid, so that a protecting group bonded to the oligonucleotide is removed, and the oligonucleotide is reacted. The oligonucleotides having the desired pattern can stacked by repeating the above operation. This method has an advantage over the PR process in that the chip can be simply produced.
A method that forms a peptide nucleic acid (PNA) array on a solid substrate by utilizing a polymer photoacid generator instead of mixing the photoacid generator into a polymer matrix has been disclosed in order to solve the above problems (see U.S. Pat. No. 6,359,125, for example).